NmCRPC COE Articles


  • [Availability of Local Therapy to Castration-Resistant Prostate Cancer for M0 Patients with Initial Prostate Specific Antigen 100 ng/ml or Higher].

    Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study.

    Published February 2, 2018
  • A Multinational, Randomised, Double-blind, Placebo-controlled, Phase III Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer


    A Multinational, Randomised, Double-blind, Placebo-controlled, Phase III Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer

    Condition: Prostate Cancer Non-Metastatic, Castration-Resistant


    • Drug: BAY1841788 (ODM-201)
    • Drug: Placebo

    Purpose: The purpose of this study is to assess the safety and efficacy of BAY1841788 (ODM-201) in patients with non-metastatic castration-resistant prostate cancer.

    Study Type: Interventional

    Clinical Trials Identifier NCT 8-digits: NCT02200614

    Sponsor: Bayer

    Primary Outcome Measures:

    • Measure: Metastasis-Free Survival
    • Time Frame: Up to 72 months
    • Safety Issue:

    Secondary Outcome Measures:

    • Measure: Overall Survival
    • Time Frame: Up to 72 months
    • Safety Issue:
    • Measure: Time to first symptomatic skeletal event (SSE)
    • Time Frame: Up to 72 months
    • Safety Issue:
    • Measure: Time to initiation of first cytotoxic chemotherapy for prostate cancer
    • Time Frame: Up to 72 months
    • Safety Issue:
    • Measure: Time to pain progression
    • Time Frame: Up to 72 months
    • Safety Issue:
    • Measure: Safety and tolerability of ODM-201
    • Time Frame: Up to 72 months
    • Safety Issue:

    Estimated Enrollment: 1500

    Study Start Date: September 12, 2014

    Phase: Phase 3


    • Age: minimum 18 Years maximum N/A
    • Gender: Male

    Inclusion Criteria:

    • Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.
    • Castration-resistant prostate cancer (CRPC) with castrate level of serum testosterone.
    • Prostate-specific antigen doubling time of ≤ 10 months and PSA > 2ng/ml.
    • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
    • Blood counts at screening: haemoglobin ≥ 9.0 g/dl,absolute neutrophil count ≥ 1500/µl, platelet count ≥ 100,000/µl.
    • Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN, creatinine ≤ 2.0 x ULN.
    • Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of the study treatment.

    Exclusion Criteria:

    • History of metastatic disease at any time or presence of detectable metastases.
    • Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation.
    • Prior treatment with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor.
    • Use of estrogens or 5-α reductase inhibitors or AR inhibitors.
    • Prior chemotherapy or immunotherapy for prostate cancer.
    • Use of systemic corticosteroid.
    • Radiation therapy within 12 weeks before randomisation.
    • Severe or uncontrolled concurrent disease, infection or co-morbidity.
    • Treatment with bisphosphonate or denosumab within 12 weeks before randomisation.
    • Known hypersensitivity to the study treatment or any of its ingredients.
    • Major surgery within 28 days before randomisation.
    • Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
    • Uncontrolled hypertension.
    • Prior malignancy.
    • Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment.
    • Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease.
    • Treatment with any investigational drug within 28 days before randomisation.
    • Any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures.


    • Bayer Clinical Trials Contact
    • +49 30 300139003


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      Llanelli Carmarthenshire SA14 8QF United Kingdom

      Romford Essex RM7 0AG United Kingdom

      Stevenage Hertfordshire SG1 4AB United Kingdom

      Maidstone Kent ME16 9QQ United Kingdom

      Preston Lancashire PR2 4HT United Kingdom

      Bebington Merseyside CH63 4JY United Kingdom

      Scunthorpe North East Lincolnshire DN15 7BH United Kingdom

      Bath Somerset BA1 3NG United Kingdom

      Stoke-on-Trent Staffordshire ST4 6QG United Kingdom

      Dudley West Midlands DY1 2HQ United Kingdom

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      Wakefield West Yorkshire WF1 4DG United Kingdom
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      Cardiff CF14 4XN United Kingdom>
      Dundee DD2 1UB United Kingdom
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    View trial on ClinicalTrials.gov

    Published March 7, 2017
  • Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

    : Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC).

    Published June 25, 2017
  • Apalutamide Delayed CRPC Metastasis by More Than 2 Years - SPARTAN

    Men with high-risk, non-metastatic, castration-resistant prostate cancer who received apalutamide, an investigational, next-generation non-steroidal androgen receptor inhibitor, survived without disease progression a median of 2 years longer than patients who received placebo in an interim analysis of the global phase III SPARTAN trial.1
    Published February 28, 2018
  • Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

    Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis.
    Published February 9, 2018
  • ARAMIS: Efficacy and Safety of Darolutamide in nmCRPC | ASCO GU 2019

    Breaking News:  Darolutamide Receives FDA Approval for the Treatment of Non-metastatic Castration-resistant Prostate Cancer

    San Francisco, CA (UroToday.com) The use of androgen-axis targeted agents, specifically enzalutamide and abiraterone, have drastically changed the landscape of advanced prostate cancer management. Just last year, at GU ASCO 2018, two landmark trials were presented – SPARTANand PROSPER - which were conducted in nonmetastatic CRPC (nmCRPC) patients.1,2 PROSPER specifically assesses enzalutamide in the M0 CRPC setting, while SPARTAN focused on apalutamide-ARN-509 (APA). Apalutamide is a next-generation competitive inhibitor of the androgen receptor under development for the treatment of patients with prostate cancer but perhaps with greater potency and reduced CNS effects. Both demonstrated ~2 year metastases-free survival benefit compared to ADT alone and there was early evidence of OS benefit.

    Published February 15, 2019
  • ASCO GU 2018: First Presentation - PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)

    San Francisco, CA (UroToday.com) Dr. Maha Hussain provided the first presentation of the phase III randomized double-blind controlled trial, the following men were eligible for inclusion:
    Published February 9, 2018
  • CUOS 2019: Treating M0 or Non-metastatic Castration-resistant Prostate Cancer

    Toronto, Ontario (UroToday.com) Dr. Neil Fleshner presented the question in debate of whether we should be treating non-metastatic castrate-resistant prostate cancer (nmCRPC) patients or wait until they have developed metastases.

    He began his discussion stating the enormous changes that have occurred in the last 15 years in the field of advanced prostate cancer. Many new treatments have been added that extend survival. These include chemotherapy (docetaxel, cabazitaxel), Sipuleucel T, androgen axis inhibitors (abiraterone, enzalutamide, apalutamide) and Radium 223. Additionally, supportive agents have been added including bone-targeted therapies (denosumab and zoledronic acid).
    Published January 11, 2019
  • Darolutamide: Approved For Non-Metastatic Castration-Resistant Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 3

    Androgen deprivation therapy (ADT) is the longstanding initial treatment for advanced hormone-sensitive prostate adenocarcinoma. Nonetheless, patients who are initiated on ADT will invariably progress by developing prostate cancer cellular clonal populations, which creates a phenotype of more castrationresistant disease with more aggressive biology.1

    Published November 5, 2019
  • Darolutamide’s FDA Rolling Submission Completed

    San Francisco, CA USA (UroToday.com) -- Orion and Bayer have announced the completion of the rolling submission of a New Drug Application (NDA) for Darolutamide to the US Food and Drug Administration (FDA).
    Published February 27, 2019
  • EAU 2019: Darolutamide Elicits a Strong PSA Response in Men with nmCRPC: Results from the ARAMIS Study

    Barcelona, Spain (UroToday.com) At EAU 2019, Teuvo Tammela, MD, PhD, presented results of the recently published ARAMIStrial. Non-metastatic (M0) CRPC (nmCRPC) is defined as a rising PSA in the setting of non-metastatic disease in the castrate state. The primary goal of treatment for these patients is the delay of metastases, considering that morbidity and mortality are both significantly worse following progression to metastases.
    Published March 18, 2019
  • ESMO 2019: Timing of Radiotherapy After Radical Prostatectomy: First Results from the RADICALS Radiotherapy Randomized Controlled Trial

    Barcelona, Spain (UroToday.com) The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. Supporters of adjuvant radiotherapy suggest that earlier treatment may be more effective, whereas those that support salvage radiotherapy suggest that this approach avoids unnecessary treatment. There are conflicting results from previous adjuvant radiotherapy trials: among 425 men with pT3N0M0 prostate cancer in SWOG S8794, those randomized to adjuvant radiotherapy had improved metastasis-free survival (MFS; HR 0.71, 95% CI 0.54-0.94) and OS (HR 0.72, 95% CI 0.55-0.96).1 However, in EORTC 22911, there was no difference in overall survival (OS) between adjuvant radiotherapy vs a wait-and-see policy (HR 1.18, 95% CI 0.91-1.53).2 At the 2019 European Society for Medical Oncology annual meeting (ESMO), prostate cancer session, Dr. Chris Parker presented the initial results of the RADICALS-RT trial, comparing the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for PSA failure.

    Published September 27, 2019
  • ESMO 2019: Updated Results from the Phase 3 SPARTAN Study, Apalutamide and Overall Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) In the phase III placebo-controlled SPARTAN study, apalutamide with ongoing androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) (HR 0.28, 95% CI, 0.23-0.35), time to symptomatic progression (HR 0.45, 95% CI 0.32-0.63), and progression-free survival on second therapy compared with placebo with ongoing ADT in patients with non-metastatic castration-resistant prostate cancer (nmCRPC).1
    Published September 27, 2019
  • FDA Approves Apalutamide, First Treatment for Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)

    Truckee, CA (UroToday.com) FDA has approved apalutamide, the first treatment for nonmetastatic castration-resistant prostate cancer, based on results from a phase 3 study that showed the drug reduced the risk of metastasis or death by 72% and improved median metastasis-free survival by more than 2 years.
    Published February 15, 2018
  • Impact of age, comorbidity, and PSA doubling time on long-term competing risks for mortality among men with non-metastatic castration-resistant prostate cancer

    Understanding competing risks for mortality is critical in determining prognosis among men with non-metastatic castration-resistant prostate cancer (nmCRPC), a disease state that often affects older men and has substantial heterogeneity in risk of cancer mortality.

    Published October 8, 2018
  • Japanese Research for Patients With Non-metastatic Castration Resistant Prostate Cancer - Enzalutamide


    Japanese Research for Patients With Non-metastatic Castration Resistant Prostate Cancer - Enzalutamide

    Condition: Prostate Cancer


    • Drug: Enzalutamide

    Purpose: The purpose of this study is to investigate the efficacy and safety of enzalutamide in patients with non-metastatic castration resistant prostate cancer. The total duration of the study will be 5 years. All patients will receive enzalutamide 160 mg (four 40 mg capsules) orally once daily. The treatment will be started at Visit 0 within one week after enrollment. Visit 1 is at 2 weeks after the treatment started; clinical assessments are conducted on adverse events and the Japanese version of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scales. Patients who are considered to be adequate by the investigator can continue the treatment with 12-week cycle visit (counted from initial dose) until patients meet withdrawal criteria. Patients will be followed up at 2 and 3 years after enrollment and at 3 years after the last participant enrollment. The end of the study is defined as follow-up assessment date at 3 years after the last participant enrollment. Patients will primarily be assessed by prostate-specific antigen (PSA) progression-free survival (PFS).

    Study Type: Interventional

    Clinical Trials Identifier NCT 8-digits: NCT02588001

    Sponsor: Translational Research Informatics Center, Kobe, Hyogo, Japan

    Primary Outcome Measures:

    • Measure: PSA-progression-free survival (PSA-PFS)
    • Time Frame: 6 years
    • Safety Issue:

    Secondary Outcome Measures:

    • Measure: Overall survival (OS)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Progression-free survival (PFS)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Metastasis free survival (MFS)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Time-to-PSA-progression (TTPP)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: PSA response rate
    • Time Frame: At week 2, and every 12 weeks for up to 6 years after initial dose
    • Safety Issue:
    • Measure: Time to first use of chemotherapy (TFC)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: QOL assessment using Japanese version of the FACT-P scales
    • Time Frame: Baseline, week 2, week 60, at withdrawal of treatment and at end of treatment for up to 6 years
    • Safety Issue:
    • Measure: Medication adherence (dosage)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Medication adherence (duration)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Medication adherence (ratio)
    • Time Frame: 6 years
    • Safety Issue:
    • Measure: Safety assessment on the incidence and severity of adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
    • Time Frame: 6 years
    • Safety Issue:

    Estimated Enrollment: 60

    Study Start Date: October 1, 2015


    • Age: minimum 20 Years maximum N/A
    • Gender: Male

    Inclusion Criteria:

    1. Patients with histologically or cytologically confirmed prostate cancer
    2. Patients with history of radical prostatectomy or radiation therapy for radical treatment
    3. Patients who receive continuous androgen deprivation therapy using both gonadotropin-releasing hormone (GnRH) agonist and antagonist, or using surgical castration
    4. Patients with serum testosterone 1.73 nmol/L (0.50 ng/dL) or less
    5. Patients with history of bicalutamide or flutamide at any time after first recurrence confirmed since radical treatment completed
    6. Patients with 3 increased PSA test results which measured consecutively at least one week apart during androgen deprivation therapy
    7. Patients with serum PSA 1 micrograms/L (1 ng/mL) or more
    8. Patients with no confirmed remote metastasis after diagnosis of prostate cancer (excluding lymph nodes metastasis with a minor axis of less than 15 mm which considered to be nonmeasurable in the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1)
    9. Patients with asymptomatic prostate cancer
    10. Patients with the Eastern Cooperative Oncology Group (ECOG) performance status 0-1
    11. Patients with life expectancy of at least 12 months
    12. Patients who have signed written informed consent to participate in this study

    Exclusion Criteria:

    1. Patients with history of any chemotherapy (including estramustine phosphate sodium hydrate (JAN)) or treatment with enzalutamide or abiraterone acetate
    2. Patients with history of steroid usage as treatment for prostate cancer
    3. Patients with history of 5-alpha-reductase inhibitor, estrogen or steroidal antiandrogen within past 4 weeks prior to initial administration of enzalutamide
    4. Patients with history of malignant tumor other than prostate cancer within past 3 years
    5. Patients with history of seizure or predisposing disease of seizure
    6. Patients with severe liver dysfunction
    7. Patients with a previous history of hypersensitivity to any component of drugs which will be administered in this study
    8. Patients who considered to be inappropriate for the study participation by the investigator.


    • Mikio Sugimoto, MD, Ph.D.
    • +81-87-898-5111


    • Kagawa University Faculty of Medicine
    • Kita-gun Kagawa-prefecture 761-0793 Japan
    • University of Miyazaki Faculty of Medicine
    • Miyazaki-city Miyazaki-prefecture 889-1692 Japan
    • Tokyo Medical Center
    • Meguro-ku Tokyo 152-8902 Japan
    • The Jikei university school of medicin
    • Minato-ku Tokyo 105-8461 Japan

    View trial on ClinicalTrials.gov

    Published June 29, 2017
  • MDACC 2018: An Update on the Treatment of M0 CRPC

    Houston, TX (UroToday.com) Within the past year the landscape of M0 CRPC has changed dramatically on the heels of 2 studies using early administration of 2nd generation androgen receptor blockers. Both apalutamide and enzalutamide have multiple inhibitor mechanisms for the AR receptor and have been accepted in the metastatic setting.
    Published November 10, 2018
  • Non metastatic CRPC: The Five Essentials - Charles Ryan

    The ASCO Genitourinary Cancers Symposium for 2018 will feature the presentation of two-phase III studies of AR directed therapy in patients with non-metastatic CRPC. Before we get these results we can reflect on why these two studies were done in this patient population in the first place, and what exact clinical need is being addressed by the development of the studies in this space. 
    Published February 1, 2018
  • The Multidisciplinary Approach to Prostate Cancer Management: From Diagnosis and Beyond

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 2

    When patients receive a diagnosis of cancer it can be devastating. Suddenly their world is turned upside down, populated by doctors, diagnostic tests, and treatments.

    The standard process for newly diagnosed patients with prostate cancer is a chronologically linear and often one-dimensional process managed by urologists.3

    Published September 5, 2017
  • Treatment Advances in Non Metastatic Castration-Resistant Prostate Cancer

    Since Drs. Huggins and Hodges demonstrated the androgen dependent nature of prostate cancer in the 1940’s, androgen deprivation therapy (ADT) has been the mainstay treatment (albeit not curative) of advanced disease.1 ADT induces a PSA decline, which may be a viable treatment for a period of time, however a patient will eventually develop a castration-resistant state by which the serum PSA level increases despite a castrate level of testosterone. The transformation to castration-resistant prostate cancer (CRPC) typically occurs before conventional imaging visualization of metastatic disease, the landmark time-point between non-metastatic (nmCRPC) and metastatic CRPC (mCRPC). 

    The PCWG3 consensus for PSA progression on ADT is the most accepted definition of nmCRPC: a 25% PSA increase from nadir (starting PSA ≥1.0 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate testosterone (< 50 ng/dL).2 The most common clinical scenario of nmCRPC is no detectable disease in the primary site, no detected lymph nodes by CT or MRI, and no disease in the bone or visceral organs.3 The most commonly used imaging for conventional detection of metastasis is a technetium-99 bone scintigraphy scan to detect bone metastases, and a CT (or MRI if CT contraindicated) of the chest, abdomen and pelvis for evaluating soft tissue metastases. Prior to the trials and data presented in this article, one in three men with nmCRPC would develop metastatic disease within 2 years.4 The objective of this article is to review the practice changing data presented in 2018 for patients with nmCRPC and discuss studies and opinions that have emerged since phase III randomized controlled trial (RCT) data was published. 

    Non Metastatic CRPC: Recent Clinical Trials

    Enzalutamide is a novel androgen receptor (AR) signaling competitive inhibitor of androgen binding. It inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment. Two large phase III trials confirmed enzalutamide efficacy and ability to improve overall survival (OS) versus placebo in men with mCRPC both in the pre-chemotherapy (PREVAIL study5,6) and post-chemotherapy (AFFIRM study7) disease state. These results set the stage for assessing efficacy of enzalutamide in early disease states. Given that enzalutamide binds the AR with a 5-8-fold greater affinity than bicalutamide, the STRIVE trial (published in 2016) was a mixed population of men diagnosed with non-metastatic (n=139) or metastatic (n=257) CRPC randomized 1:1 to receive enzalutamide (160 mg/day) or bicalutamide (50 mg/day), with both arms remaining on ADT.8 Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (HR 0.24, 95%CI 0.18-0.32), as well as demonstrated significant improvements in all key secondary end points: time to PSA progression (HR 0.19, 95%CI 0.14-0.26), proportion of patients with a ≥ 50% PSA response (81% v 31%; P < .001), and radiographic progression free survival (PFS) in metastatic patients (HR 0.32, 95%CI 0.21-0.50). Importantly, these beneficial effects with enzalutamide were observed in both the nonmetastatic and metastatic subgroups. Even before results of the STRIVE trial were published, recruitment was already underway for two large phase III trials that would report in 2018 and change clinical practice for men with nmCRPC: the PROSPER and SPARTAN trials. 

    The PROSPER trial was an international, double-blind, randomized, placebo-controlled, phase 3 trial approved at more than 300 sites in 32 countries.9 In this trial, 1,401 patients with nmCRPC were randomized 2:1 to enzalutamide vs placebo, with a primary outcome of metastasis-free survival (MFS). Secondary endpoints were time to PSA progression, time to first use of new therapy, and OS. The median MFS was 36.6 months in the enzalutamide arm versus 14.7 months in the placebo group: a 71% improvement for men receiving enzalutamide (HR 0.29, 95%CI 0.24-0.35). Time to PSA progression was 37.2 months for the enzalutamide group vs 3.9 months for the placebo arm (HR 0.07, 95%CI 0.05-0.08), and time to subsequent therapy was 39.6 months for enzalutamide patients compared to 17.7 for the placebo group (HR 0.21, 95%CI 0.17-0.26). At the interim analysis for OS, the HR was 0.80 (favoring enzalutamide), but was not statistically significant (p=0.15).

    Apalutamide is a nonsteroidal anti-androgen AR inhibitor, which binds to the ligand-binding domain of the AR after nuclear translocation; apalutamide has a 7-10-fold higher affinity for the AR than bicalutamide. The SPARTAN trial was a multi-institutional, double-blind, randomized, placebo-controlled, phase 3 trial at 332 sites in 26 countries in North America, Europe, and Asia-Pacific region.10 This trial randomized 1,207 men 2:1 to receive apalutamide vs placebo. In the planned primary analysis at 378 events, median MFS was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR for metastasis or death 0.28, 95% CI 0.23-0.35). Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR 0.45, 95%CI 0.32-0.63). The conclusions from SPARTAN were that apalutamide decreased the risk of metastasis or death by 72% and prolonged the median MFS by more than two years in men with high-risk nmCRPC. Furthermore, the MFS benefit was consistent across all subgroups, and the results were supported by consistent improvement across all evaluable endpoints: time to metastasis, PFS, time to symptomatic progression, time to PSA progression, and PSA decline.

    Non Metastatic CRPC Since PROSPER and SPARTAN

    Following presentation of the SPARTAN trial at the GU ASCO annual meeting in February 2018 and concomitant publication in The New England Journal of Medicine (NEJM)10, the FDA moved quickly on February 14, 2018 to approve apalutamide (240 mg daily) for men with nmCRPC. The PROSPER trail was also published in NEJMin June 20189, and enzalutamide (160 mg daily) also gained FDA approval on July 13, 2018. 

    Prior to FDA approval of enzalutamide, the American Urological Association (AUA) provided an amendment to their AUA CRPC Guideline11, first presented at the AUA 2018 annual meeting. This amendment focused solely on Index Patient 1—patients with non-metastatic CRPC, providing four updated Guideline Statements11:
    • Guideline Statement 1:Clinicians should offer apalutamide or enzalutamide with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease (Standard; Evidence Level Grade A [apalutamide]/Grade B [enzalutamide])
    • Guideline Statement 2:Clinicians may recommend observation with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies (Recommendation; Evidence Level Grade C)
    • Guideline Statement 3:Clinicians may offer treatment with a second-generation androgen synthesis inhibitor (i.e. abiraterone + prednisone) to select patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies and are willing to accept observation (Option; Evidence Level Grade C)
    • Guideline Statement 4:Clinicians should not offer systemic chemotherapy or immunotherapy to patients with non-metastatic CRPC outside the context of a clinical trial (Recommendation; Evidence Level Grade C)
    Based on data from PROSPER and SPARTAN, clinicians are now equipped with two FDA approved agents for prescribing to patients with nmCPRC. However, in the absence of a head-to-head trial (which is unlikely), the comparative efficacy and toxicity of these two agents was the basis for an indirect treatment comparison of apalutamide and enzalutamide recently published in European Urologic Oncology. For this study, Wallis et al. 12 pooled data from PROSPER and SPARTAN resulting in 2,608 patients of whom 806 received apalutamide, 933 received enzalutamide, and 869 received placebo, in addition to ongoing ADT. Study methodology and inclusion criteria were similar between studies though PROSPER required a serum PSA level ≥2ng/mL while no such requirement was present in the SPARTAN trial. Despite this difference in study inclusion criteria, the patients in the two study cohorts had similarly aggressive disease characteristics with median PSADT in both studies between 3 and 5 months.

    As noted above, both apalutamide (HR 0.28, 95% CI 0.23-0.35) and enzalutamide (HR 0.29, 95% CI 0.24-0.35) demonstrated statistically significant improvements in MFS compared with placebo. On indirect comparison of apalutamide and enzalutamide, there was no significant difference in MFS between the two agents (HR 1.04, 95% CI 0.78-1.37). Similarly, there were no significant differences in time to PSA progression, OS, any AEs, serious AEs, or AEs leading to treatment discontinuation. The authors concluded that while indirect comparisons cannot supplant direct comparative data, the analysis suggests that apalutamide and enzalutamide are similarly effective in delaying metastases for patients with nmCRPC.

    Since indirect comparison between enzalutamide and apalutamide demonstrated no appreciable difference in efficacy or toxicity, subsequent studies and editorials have focused on  several initiatives, including quality of life. In a letter to the NEJM editor, Rachner and colleagues noted that patients receiving apalutamide had a higher rate of bone fracture (11.7%) compared to placebo (6.5%)13, noting that only 10% of patients in SPARTAN received bone-protective therapy at the beginning of the trial. In the author’s response to this editorial, Smith et al. noted that patients treated with enzalutamide in the PROSPER trial had a higher rate of falls and fractures than the placebo patients, attributing these findings to a medication case effect. 14 This dialogue highlights the NCCN guideline recommendations to assess for fracture risk and treat with a bisphosphonate or denosumab when the absolute fracture risk warrants drug therapy.

    Specific health-related quality of life (HRQOL) data from both trials has also been presented since original publication of the phase III trials. The SPARTAN trial collected Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaire data at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter.15 Notably, FACT-P and EQ-5D-3L scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for American adult men. Furthermore, group mean patient-reported outcome scores over time showed that HRQOL was maintained from baseline after initiation of apalutamide and similar over time. Mean change from baseline analysis showed that HRQOL deterioration was more apparent in the placebo group than those receiving apalutamide. The SPARTAN investigators noted that in addition to improved MFS and time to symptomatic progression compared to men receiving placebo, they achieved these improved outcomes while preserving quality of life.

    Similarly, PROSPER has reported results of HRQOL and pain evaluations.16 FACT-P and Brief Pain Inventory, Short Form, were used to assess HRQOL and pain at baseline and every 16 weeks during treatment. The authors defined pain progression as ≥2 points in pain severity items and mean scores increase from baseline. Baseline characteristics and scores were similar between the enzalutamide and placebo arms with low pain (median 0) and high HRQoL (median FACT-P total score: 121). Decrease in attrition rate was greater in the placebo arm (53%) compared to the enzalutamide arm (68%), mainly due to disease progression at week 49. Most patients reported no change or improvement in HRQoL. The proportion of patients with pain progression at week 49 was similar between those receiving enzalutamide (11–20%) and placebo (14–21%). There was a non-statistically significant lower risk of pain progression observed with enzalutamide vs. placebo in the confirmed analysis (HR 0.78–0.93, p > 0.05). Furthermore, there was a statistically significant lower risk of deterioration observed for patients receiving enzalutamide for FACT-P total (HR 0.83, 95%CI 0.69-0.99), FACT Advanced Prostate Symptom Index (HR 0.79, 95%CI 0.65-0.94), prostate cancer subscale (HR 0.79, 95%CI 0.67-0.93), and emotional well-being (HR 0.69, 95%CI 0.55-0.86). Taking HRQOL data together from both PROSPER and SPARTAN, enzalutamide and apalutamide are both associated with maintaining quality of life throughout the trial follow-up.


    2018 has been a landmark year for advancing treatment options for patients with nmCRPC, with two phase III RCTs reporting unprecedented hazard ratios for delaying metastasis for patients treated with enzalutamide and apalutamide. Since initial trial publication, HRQOL studies have confirmed maintenance of quality of life on these medications, although there may be concerns for increased risk of bone fracture combining these powerful AR targeted agents with ADT. Looking forward, the ongoing ARAMIS trial assessing darolutamide (another AR pathway inhibitor) in patients with nmCRPC (with similar inclusion criteria and outcomes as PROSPER and SPARTAN) may provide clinicians with another agent in the medical armamentarium for treatment of nmCRPC. This trial has an estimated completion date of September 2018.
    Written by: Zachary Klaassen, MD
    References: 1. Huggins C, Hodges CV. Studies on prostate cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-7.
    2. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402-18.
    3. Mateo J, Fizazi K, Gillessen S, Heidenreich A, Perez-Lopez R, Oyen WJG, et al. Managing Nonmetastatic Castration-resistant Prostate Cancer. Eur Urol. 2018.
    4. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23:2918-25.
    5. Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017;71:151-4.
    6. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-33.
    7. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.
    8.  Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol. 2016;34:2098-106.
    9. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018;378:2465-74.
    10. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378:1408-18.
    11. Lowrance WT, Murad MH, Oh WK, Jarrard DF, Resnick MJ, Cookson MS. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol. 2018.
    12. Wallis CJD, Chandrasekar T, Goldberg H, Klotz L, Fleshner N, Satkunasivam R, et al. Advanced Androgen Blockage in Nonmetastatic Castration-resistant Prostate Cancer: An Indirect Comparison of Apalutamide and Enzalutamide. European Urology Oncology. 2018;1:238-41.
    13. Rachner TD, Tsourdi E, Hofbauer LC. Apalutamide and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378:2541-2.
    14. Smith MR, Yu MK, Small EJ. Apalutamide and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378:2542.
    15. Saad F, Cella D, Basch E, Hadaschik BA, Mainwaring PN, Oudard S, et al. Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018.
    16. Attard G, Saad F, Tombal B, Hussain M, Sternberg CN, Phung D, et al. Health-related quality of life (HRQoL) deterioration and pain progression in men with non-metastatic castration-resistant prostate cancer (M0 CRPC): Results from the PROSPER study. J Clin Oncol. 2018;36:abstr 5010.
    Published April 16, 2019
  • Using prognosis to guide early detection and treatment selection in non-metastatic prostate cancer.

    Over recent years there has been an increasing awareness that our ideas on the lethality of primary non-metastatic prostate cancer may need to change. This concept has emerged from a number of different sources including randomised controlled trials, reports from mature active surveillance programmes and prognostic modelling work in large populations (1-2).

    Published December 5, 2018